Silent mutation gets its say

There are 64 possible three-letter combinations of the four DNA bases that are the building blocks of the genetic code, but only 20 amino acids that are the building blocks of proteins. Some amino acids can be coded for by several different three-base combinations – for example, the triplets ACA, ACC, ACG and ACT all code for the amino acid threonine. When one of those bases changes, the resulting single-nucleotide polymorphism is called synonymous (sSNP). It has been assumed that sSNPs have no effect on proteins. Now, researchers from the German University of Hamburg and the British University of Bristol have shown that a change from ACT to ACG in the cystic fibrosis transmembrane conductance regulator (CFTR) affected CFTR function. The ACG codon interacted with a relatively rare transfer RNA, slowing down CFTR production and affecting folding. The authors concluded that sSNPs "introduce variability into an individual's genome composition, which might influence disease risk, the spectrum of disease symptoms and, ultimately, therapeutic response." They published their findings in the May 16, 2017, issue of PLoS Biology.

Targeting KRAS with miRNA

The RAS family is the most frequently mutated oncogene family, and it is mutated in almost all pancreatic tumors, more than half of all colorectal tumors, and a sizable fraction of lung tumors. But efforts to drug the RAS family – particularly KRAS – have not yielded any clinically used agents to date. Now, researchers from Ohio State University and Virginia Commonwealth University have identified a microRNA that specifically inhibited mutated but not wild-type forms of KRAS. Allowing normal forms of KRAS to continue doing their work while blocking mutated forms has been a major challenge in developing KRAS inhibitors. The authors said that "our methodology for the design of artificial noncoding RNAs can be used to effectively and exclusively target point-mutated KRAS. The application of such a design technique can be extended to other point-mutated oncogenes and to other diseases caused by point-mutation gain of function, providing a major advantage compared with other RNA-based therapies." The team published its findings in the May 8, 2017, online issue of the Proceedings of the National Academy of Sciences.

. . . And with activators

Another team, from Case Western University, has used an alternate strategy to interfere with KRAS. Instead of targeting KRAS directly, the team developed a small-molecule activator of the tumor suppressor PP2A. Treatment with PP2A activators "inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models," the authors wrote. "Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases." Activators are in general more difficult to develop than inhibitors, and the findings represent "an advancement toward the development of small-molecule activators of tumor suppressor proteins." Their findings appeared in the May 15, 2017, online issue of the Journal of Clinical Investigation.

Ruling CSCs with an iron fist

The antibiotic compound salinomycin, a natural compound that is produced by Streptomyces bacteria, is also effective against cancer stem cells (CSCs). Researchers from the French INSERM Institute and Institut Curie have shown that ironomycin (AM5), a synthetic derivative of salinomycin, was more effective against CSCs than salinomycin itself, and that it acted by sequestering iron in cellular lysosomes. That sequestration triggered cellular pathways that led to further accumulation of iron in lysosomes, ultimately leading to the production of reactive oxygen species that damage the lysosomes and set off cell death programs. "These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells," the authors concluded. Their work appeared in the May 15, 2017, online issue of Nature Chemical Biology.

Metformin rescues fragile X

Treatment with the generic diabetes drug metformin reversed symptoms of fragile X syndrome (FXS) in adult mouse models of the disease, suggesting that the drug could be rapidly repurposed for the treatment of FXS, which is the most common monogenic cause of mental retardation and whose symptoms include autism-like behavior. Researchers from the Canadian McGill University decided to look at the effects of metformin on FXS because metformin suppresses pathways that are deregulated in FXS. They found that 10 days of treatment with metformin normalized behavioral and cognitive symptoms in the mice, though it had no effect on activity levels. The most likely mechanism of action is the suppression of matrix metalloproteinase 9 expression in the brain, though the authors cautioned that "we cannot exclude the possibility of an unidentified, peripherally mediated rescue mechanism, given that metformin inhibits gluconeogenesis and alters the gut microbiota." Their work appeared in the May 15, 2017, issue of Nature Medicine.

Sex hormones affect asthma risk

Male sex hormones inhibited the development of group 2 innate lymphoid cells (ILC2s), a key player in allergic asthma. Women are more likely to develop asthma than men, for unknown reasons to date. Researchers from the French INSERM Institute and the Australian Walter and Eliza Hall Institute of Medical Research showed that ILC2 progenitor cells expressed the androgen receptor, and testosterone suppressed their development into ILC2s in response to the proinflammatory cytokine interleukin-33. The researchers concluded that "androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33." The findings appeared in the May 8, 2017, online issue of the Journal of Experimental Medicine.

Finishing school makes starter cells

Two separate groups of researchers have generated blood-forming stem cells that could be used in research studies, drug screening and ultimately cell therapy. A team from Weill Cornell Medical College generated the stem cells from adult mouse blood vessel endothelial cells, while a team from Boston Children's Hospital converted human pluripotent stem cells first into hematogenic endothelial cells and then into hematopoietic stem cells. Both teams used a cocktail of transcription factors, followed by either transplantation into the bone marrow or co-culturing with endothelial cells. As yet unknown signals from the final step allowed the cells to turn into hematopoietic stem cells that were able to generate all types of blood cells after transplantation, albeit in low numbers. The papers appeared together in the May 17, 2017, online issue of Nature.

Broadly neutralizing Abs to Ebola

As the recent report of new cases of Ebola virus disease in the Democratic Republic of Congo has demonstrated once again, Ebola remains a public health threat even in the absence of current large-scale epidemics. Independent research teams have identified broadly neutralizing antibodies to Ebolavirus as well as related filoviruses, offering both the possibility for simpler passive antibody treatments and new strategies for vaccine design. Strongly neutralizing antibodies for specific strains of Ebolavirus have been identified, but treatment has necessitated antibody cocktails because broadly neutralizing antibodies had eluded researchers to date. A team from Mapp Biopharmaceutical Inc., the U.S. Army Medical Research Institute of Infectious Diseases, and the Albert Einstein College of Medicine profiled the antibody response of a human Ebola survivor and identified an antibody that conferred protection against Ebola virus, Sudan virus and Bundibugyo virus – all related filoviruses – when administered to mice. Another team, from the University of Maryland and Integrated Biotherapeutics Inc., was able to stimulate production of an antibody in macaque monkeys that neutralized Ebola, Sudan, Bundibugyo and Reston viruses. Both antibodies target the fusion glycoprotein of Ebolavirus, and the findings collectively "have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails," the University of Maryland/Integrated Biotherapeutics authors wrote. The papers appeared in the May 18, 2017, issue of Cell.

BBB transport behind neurological syndrome

Failure of tyrosine hydroxylase (TH) to cross the blood-brain barrier (BBB) underlies the development of Allan-Herndon-Dudley syndrome, which is characterized by both intellectual disability and movement disorders. The syndrome is caused by mutations in the TH transporter MCT8, but animal models do not recapitulate the symptoms of the human disorders. Researchers at the University of Wisconsin and Cedars-Sinai Medical Center developed a model of the syndrome using human induced pluripotent stem cells and found that while neurons lacking the MCT8 transporter functioned normally, its presence was critical in endothelial cells of the BBB. "Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy," the authors concluded. They published their findings in the May 16, 2017, online issue of Cell Stem Cell.

Brain controls breath in heart failure

Problems with breathing are a consequence of heart failure (HF) that is frequent and ranges from frightening to fatal in its consequences. Breathing problems result from weakening of the diaphragm muscle, but research has focused on the later stages of such weakening. Canadian researchers from the University of Guelph and Dalhousie Medicine wanted to understand the cause of the weakening. The authors showed that diaphragm atrophy started in the brain, due to an interaction of angiotensin and beta-adrenergic signaling that resulted in "a chronically higher work-of-breathing in HF, independent of changes in lung mechanics or the presence of pulmonary edema." That constant overdrive ultimately led to atrophy of the diaphragm, but focusing on the diaphragm atrophy was not an effective therapeutic strategy in mouse models. Instead, "only drugs that were able to penetrate the blood-brain barrier were effective in treating ventilatory overdrive and preventing diaphragmatic atrophy." The team published its findings in the May 17, 2017, issue of Science Translational Medicine.